Abstract
Bistable epigenetic switches are fundamental for cell fate determination in unicellular and multicellular organisms. Regulatory proteins associated with bistable switches are often present in low numbers and subject to molecular noise. It is becoming clear that noise in gene expression can influence cell fate. Although the origins and consequences of noise have been studied, the stochastic and transient nature of RNA errors during transcription has not been considered in the origin or modeling of noise nor has the capacity for such transient errors in information transfer to generate heritable phenotypic change been discussed. We used a classic bistable memory module to monitor and capture transient RNA errors: the lac operon of Escherichia coli comprises an autocatalytic positive feedback loop producing a heritable all-or-none epigenetic switch that is sensitive to molecular noise. Using single-cell analysis, we show that the frequency of epigenetic switching from one expression state to the other is increased when the fidelity of RNA transcription is decreased due to error-prone RNA polymerases or to the absence of auxiliary RNA fidelity factors GreA and GreB (functional analogues of eukaryotic TFIIS). Therefore, transcription infidelity contributes to molecular noise and can effect heritable phenotypic change in genetically identical cells in the same environment. Whereas DNA errors allow genetic space to be explored, RNA errors may allow epigenetic or expression space to be sampled. Thus, RNA infidelity should also be considered in the heritable origin of altered or aberrant cell behaviour.
Highlights
Altered proteins can result from errors incurred at any step during information transfer from DNA to protein
Errors that occur during RNA transcription are considered transient, because the life span of mRNAs and their encoded proteins is thought to be too short to have heritable consequences
We show that transient errors that arise during transcription can cause a heritable phenotypic change within a population of genetically identical Escherichia coli cells growing in the same environment
Summary
Altered proteins can result from errors incurred at any step during information transfer from DNA to protein. Errors in DNA, RNA, and protein synthesis occur at rates of, very roughly, 10À9, 10À5, and 10À4 errors per residue, respectively [1]. Errors in DNA synthesis can be fixed as permanent errors—mutations—which can generate heritable change in cellular phenotype. Transcription and translation errors occur more frequently, but are considered transient and their effects fleeting, since the altered molecules are present for a limited time. It has been shown that transcription over a damaged DNA template can generate altered proteins in nondividing DNA repair– deficient cells [2], and it has been suggested that transient errors can produce transient mutators, thereby generating phenotypic change by introducing mutations [3,4]. The capacity for transient errors to generate heritable epigenetic phenotypic change has not been considered
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